biostudies-literatureGu LNCATS NIH HHSNIDDK NIH HHSNIA NIH HHSNIEHS NIH HHSNCI NIH HHSNIH HHS461-469https://www.ebi.ac.uk/biostudies/studies/S-EPMC12168545biostudies-literatureUnknown637(8045)Hepatocellular carcinoma (HCC) originates from differentiated hepatocytes undergoing compensatory proliferation in livers damaged by viruses or metabolic-dysfunction-associated steatohepatitis (MASH)¹. While increasing HCC risk², MASH triggers p53-dependent hepatocyte senescence³, which we found to parallel hypernutrition-induced DNA breaks. How this tumour-suppressive response is bypassed to license oncogenic mutagenesis and enable HCC evolution was previously unclear. Here we identified the gluconeogenic enzyme fructose-1,6-bisphosphatase 1 (FBP1) as a p53 target that is elevated in senescent-like MASH hepatocytes but suppressed through promoter hypermethylation and proteasomal degradation in most human HCCs. FBP1 first declines in metabolically stressed NatureFBP1 controls liver cancer evolution from senescent MASH hepatocytes.PMC12168545S10 OD032398R01 DK120714R01 DK137061P01 AG073084P01 CA281819R01 ES030993KL2 TR001444R01 CA234128R01 ES032547R35 CA220483R01 CA281784R01 DK133930R01 DK099205R01 DK133448R01 CA269919P30 CA023100P30 DK120515Nandi SPGanguly SZhu YLee MCarter KWDhar DLiver Cancer CollaborativeLiu YWinteringham LNWallace MCGu LTibballs JSimon MCCarlessi RSauceda CAlexandrov LBLeedman PJTeneche MGAdams PDDwyer BJOhira MHosseini MSakane SKisseleva TWatari KBareng BGonzalez DJTirnitz-Parker JEEForrest ARRKarin MfalseFBP1 controls liver cancer evolution from senescent MASH hepatocytes.Hepatocellular carcinoma (HCC) originates from differentiated hepatocytes undergoing compensatory proliferation in livers damaged by viruses or metabolic-dysfunction-associated steatohepatitis (MASH)¹. While increasing HCC risk², MASH triggers p53-dependent hepatocyte senescence³, which we found to parallel hypernutrition-induced DNA breaks. How this tumour-suppressive response is bypassed to license oncogenic mutagenesis and enable HCC evolution was previously unclear. Here we identified the gluconeogenic enzyme fructose-1,6-bisphosphatase 1 (FBP1) as a p53 target that is elevated in senescent-like MASH hepatocytes but suppressed through promoter hypermethylation and proteasomal degradation in most human HCCs. FBP1 first declines in metabolically stressed 2025-01-01T00:00:00Z2025 Jan2026-06-02T08:42:04.228Z2026-04-16T03:12:30.149ZS-EPMC121685453974358510.1038/s41586-024-08317-9